WO1997032588A2 - Kombination von dehydroepiandrosteron und aromatasehemmern und verwendung dieser kombination zur herstellung eines arzneimittels zur behandlung eines relativen und absoluten androgenmangels beim mann - Google Patents

Kombination von dehydroepiandrosteron und aromatasehemmern und verwendung dieser kombination zur herstellung eines arzneimittels zur behandlung eines relativen und absoluten androgenmangels beim mann Download PDF

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Publication number
WO1997032588A2
WO1997032588A2 PCT/DE1997/000518 DE9700518W WO9732588A2 WO 1997032588 A2 WO1997032588 A2 WO 1997032588A2 DE 9700518 W DE9700518 W DE 9700518W WO 9732588 A2 WO9732588 A2 WO 9732588A2
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WO
WIPO (PCT)
Prior art keywords
combination
men
dhea
testosterone
dehydroepiandrosterone
Prior art date
Application number
PCT/DE1997/000518
Other languages
German (de)
English (en)
French (fr)
Other versions
WO1997032588A3 (de
Inventor
Jörg Elliesen
Albert Radlmaier
Ursula Habenicht
Friedmund Neumann
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP97920511A priority Critical patent/EP0885005B1/de
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to US09/142,226 priority patent/US6696432B1/en
Priority to JP9531360A priority patent/JP2000506844A/ja
Priority to DK97920511T priority patent/DK0885005T3/da
Priority to DE59710660T priority patent/DE59710660D1/de
Priority to AU26902/97A priority patent/AU730777B2/en
Priority to IL12582197A priority patent/IL125821A0/xx
Priority to PL97328709A priority patent/PL328709A1/xx
Priority to BR9707844A priority patent/BR9707844A/pt
Priority to AT97920511T priority patent/ATE247968T1/de
Publication of WO1997032588A2 publication Critical patent/WO1997032588A2/de
Publication of WO1997032588A3 publication Critical patent/WO1997032588A3/de
Priority to NO984075A priority patent/NO984075L/no

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens

Definitions

  • the invention relates to a combination of dehydroepiandrosterone and aromatase inhibitors and the new use of dehydroepiandrosterone (DHEA) in combination with aromatase inhibitors for the manufacture of a medicament for the treatment of a relative and / or absolute androgen deficiency in men
  • the hormonal milieu of the sex steroids is characterized by a clear overweight of androgens over estrogens. While the main circulating component of androgens, testosterone, is detected in the serum in units in the range of nmol / 1, the estrogen counterpart, ostradiol, is only found in Measured range of pmol / 1 This significant overweight of androgens is generally detectable in the entire post-pubertal life span, but there is a clearly different expression of this androgen dominance depending on age.
  • Table 1 shows published measurement series in which the ratio of serum testosterone to serum ostradiol was determined in comparison of young to older (> 60 years) men Table 1 Comparison of serum T / E2 ratio in young and older men
  • the resulting relative testosterone deficit can have an unfavorable effect in many respects.
  • BPH benign prostatic hyperplasia
  • the effects of estrogens however, the relative testosterone deficit per se can be held responsible for a number of age-related disorders.
  • a testosterone derivative i.e. no natural testosterone
  • DHT dihydrotestosterone
  • the extent of the counter-regulatory potential can be estimated from the experience with the use of pure antiandrogens in patients with prostate cancer who belong to the same age group as patients with climacteric virile. If the central inhibitory effect of androgens is prevented by pure antiperspirants such as flutamide or Casodex, there is a counterregulatory increase in the serum testosterone concentration by approximately 50-60% compared to the initial value in this age group. In the case of treatment lasting for months, however, the prostate carcinoma patients treated with pure antiandrogens showed signs of a decrease in the activity of the counter-regulation, i.e.
  • anti-estrogens seem to be of little use for the treatment of a relative androgen deficiency in men.
  • a treatment with anti-estrogens has no influence on the estrogen level, since these block the action of the estrogens at their receptor. If anti-estrogens are used as receptor blockers, inadequate compliance immediately led to the most unfavorable effect, since the higher estrogen concentration can act directly on the newly released receptors due to the onset of counter-regulation.
  • Another disadvantage of anti-estrogen treatment is the uncertainty as to whether the blockade of estrogen receptors is equally pronounced in all estrogen-dependent tissues and organs and the importance of intrinsic estrogenicity, e.g. which has the best known anti-estrogen tamoxifen, for use in men.
  • the object of the present invention is to provide suitable substances which remedy a relative androgen deficiency (hypoandrogenism) in men while simultaneously approaching the physiological hormonal ratio of androgens to estrogens and which avoid the disadvantages mentioned.
  • DHEA dehydroepiandrosterone
  • aromatase inhibitors by using at least one aromatase inhibitor with DHEA for the manufacture of a medicament for the treatment of a relative androgen deficiency in men. It has been found that the use of a combination of DHEA and at least one aromatase inhibitor in the treatment of relative androgen deficiency in older men leads to a long-term increase in androgen levels.
  • the pharmaceutical combination preparation according to the invention can be used in further indications which result from the lack of DHEA and the androgens subsequent in steroid biosynthesis.
  • DHEA effects in the animal model and on humans are described for DHEA alone. These include antiproliferative effects, immunomodulatory effects, effects on carbohydrate and lipid metabolism, on body weight, fat mass and muscle mass, on coagulation, effects in the sense cardioprotection, effects on the central nervous system, on mitochondrial cell respiration, and a protective effect of the cell against oxygen radical formation.
  • Aromatase inhibitors for the purposes of the present invention are all those compounds which inhibit the formation of estrogens from their metabolic precursors Prevent enzyme aromatase (inhibition of biosynthesis). Aromatase inhibitors are therefore all compounds which are suitable as substrates for aromatase, such as that in the Journal of Clinical Endocrinology and Metabolism. 49, 672 (1979) described testolactone (17a-oxa-D-homoandrost-l, 4-diene-3, 17-dione), which is described in "Endocrinology” 1973. Vol. 92, no. 3, page 874 described connections
  • Selective aromatase inhibitors are preferably used in the DHEA / aromatase inhibitor combination and for the manufacture of a medicament for the treatment of a relative androgen deficiency (hypoandrogenism) in men according to the present invention.
  • Selective aromatase inhibitors are to be understood as meaning those compounds which act as a substrate for the aromatase and, in the dosage used, do not influence other enzymes in a clinically relevant manner apart from the aromatase.
  • the typical selective aromatase inhibitors according to the present invention are, for example, the steroidal compounds l-methyl-androsta-1,4-diene-3,17-dione (DE-A 33 22 285; atamestane),
  • Tables 3 and 4 show the results after 48 weeks of treatment Table 3: Testosterone serum concentration (ng / ml) under atamestane
  • testosterone dominance which is 30 - 50% lower in the age group of patients over the age of 60 compared to the younger age groups, causes the symptoms of the "male climacteric"
  • the goal is to restore the original "balance of power" between androgens and estrogens by the administration of a, preferably selective, aromatase inhibitor by stimulating endogenous testosterone substitution without the need for an exogenous supply of androgens.
  • the relation prevailing in old age is the result of a 30-50% reduction compared to the adolescent values, ie is still 50-70% of the previous value
  • the corresponding "adolescent" preliminary value can be calculated for each individual patient.
  • DHEA dehydroepiandrosterone
  • DHEA and the steroid hormones that follow in androgen biosynthesis also have their own pharmacological effect, they can be used in combination with an aromatase inhibitor without increasing estrogen biosynthesis, which is undesirable in men.
  • DHEA is used in combination in a daily amount of 10 mg to 100 mg, preferably 20 mg to 60 mg, if the idea of substitution is in the foreground.
  • DHEA dosages are of the order of up to 1000 mg within the scope of the present invention
  • 25 to 500 mg, preferably 50 to 250 mg, atamestane or a biologically equivalent amount of another aromatase inhibitor are used daily in the combination according to the invention for the treatment of a relative or absolute lack of androgen in men.
  • DHEA and the aromatase inhibitors can e.g. B. orally or parenterally.
  • tablets, dragees, capsules, pills, suspensions or solutions are particularly suitable, which can be prepared in a customary manner known to the person skilled in the art with the additives and carrier substances customary in galenics for the formulation of aromatase inhibitors to be administered orally.
  • DHEA and the aromatase inhibitor can be formulated together or separately. If the formulation is separate, sequential administration is also conceivable.
  • the medicament produced according to the invention contains, as the active ingredient per unit dose, the aromatase inhibitor atamestane in a dosage of 25 to 250 mg in addition to the usual auxiliaries, carriers and / or diluents or other aromatase inhibitors in a biologically equivalent effective dosage.
  • DHEA is contained in the common or in a separate dose unit in an amount of 5 to 200 mg in addition to the usual excipients.
  • Example 2 A typical composition for a formulation of the aromatase inhibitor atamestane with DHEA as a tablet is shown in Example 2 below.
  • DHEA 50 mg of DHEA and 100 mg of atamestane are administered orally daily. There are 100 older men aged 70 or over who have been randomly divided into four treatment groups. You receive either DHEA (50 mg / day) or atamestane (100 mg / day) or DHEA + atamestane or placebo for 36 weeks and are then followed up for half a year.
  • the estrogen concentration is effectively reduced and an undesirable increase in estrogen levels is effectively suppressed by the DHEA substitution.
  • the easy controllability of the therapy distinguishes the treatment with DHEA and an aromatase inhibitor to stimulate endogenous testosterone production compared to the use with anti-estrogens.
  • prospective control of therapy by early measurement of pharmacodynamic parameters is not possible with anti-estrogens.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)
PCT/DE1997/000518 1996-03-06 1997-03-06 Kombination von dehydroepiandrosteron und aromatasehemmern und verwendung dieser kombination zur herstellung eines arzneimittels zur behandlung eines relativen und absoluten androgenmangels beim mann WO1997032588A2 (de)

Priority Applications (11)

Application Number Priority Date Filing Date Title
AU26902/97A AU730777B2 (en) 1996-03-06 1997-03-06 Combination of dehydroepiandrosterone and aromatase inhibitors and use of this combination for the production of a pharmaceutical agent for treating a relative and absolute androgen deficiency in men
US09/142,226 US6696432B1 (en) 1996-03-06 1997-03-06 Combination of dehydroepiandrosterone and aromatase inhibitors and use of this combination to produce a medicament for treating relative and absolute androgen deficiency in men
JP9531360A JP2000506844A (ja) 1996-03-06 1997-03-06 男性の相対及び絶対的アンドロゲン欠乏症を治療する医薬の製造に用いるデヒドロエピアンドロステロン及びアロマターゼ阻害剤の複合、並びにこの複合の使用
DK97920511T DK0885005T3 (da) 1996-03-06 1997-03-06 Anvendelse af dehydroepiandrosteron og aromatasehæmmere til fremstilling af et lægemiddel til behandling af en relativ og absolut androgenmangel hos mænd
DE59710660T DE59710660D1 (de) 1996-03-06 1997-03-06 Kombination von dehydroepiandrosteron und aromatasehemmern und verwendung dieser kombination zur herstellung eines arzneimittels zur behandlung eines relativen und absoluten androgenmangels beim mann
EP97920511A EP0885005B1 (de) 1996-03-06 1997-03-06 Kombination von dehydroepiandrosteron und aromatasehemmern und verwendung dieser kombination zur herstellung eines arzneimittels zur behandlung eines relativen und absoluten androgenmangels beim mann
IL12582197A IL125821A0 (en) 1996-03-06 1997-03-06 A pharmaceutical composition containing dehydroepiandrosterone and aromatase inhibitors and use thereof
AT97920511T ATE247968T1 (de) 1996-03-06 1997-03-06 Kombination von dehydroepiandrosteron und aromatasehemmern und verwendung dieser kombination zur herstellung eines arzneimittels zur behandlung eines relativen und absoluten androgenmangels beim mann
BR9707844A BR9707844A (pt) 1996-03-06 1997-03-06 Combinação de desidroepiandrosterona e inibidores de aromatase e emprego desta combinação para a preparação de um medicamento para o tratamento de uma deficiência de androgênio relativa e absoluta no homem
PL97328709A PL328709A1 (en) 1996-03-06 1997-03-06 Mixture of dehydroepiandrosterone and aromatase inhibiting substances and application of such mixture in production of a therapeutic agent for treating relative and absolute hypoadrogenalaemia among male patients
NO984075A NO984075L (no) 1996-03-06 1998-09-04 Kombinasjon av dehydroepiandrosteron og aromatasehemmere og anvendelse av denne kombinasjon for fremstilling av et legemiddel for behandling av en relativ og absolutt androgen mangel hos menn

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19610645A DE19610645A1 (de) 1996-03-06 1996-03-06 Kombination von Dehydroepiandrosteron und Aromatasehemmern und Verwendung dieser Kombination zur Herstellung eines Arzeimittels zur Behandlung eines relativen und absoluten Androgenmangels beim Mann
DE19610645.1 1996-03-06

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WO1997032588A2 true WO1997032588A2 (de) 1997-09-12
WO1997032588A3 WO1997032588A3 (de) 1997-10-16

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PCT/DE1997/000518 WO1997032588A2 (de) 1996-03-06 1997-03-06 Kombination von dehydroepiandrosteron und aromatasehemmern und verwendung dieser kombination zur herstellung eines arzneimittels zur behandlung eines relativen und absoluten androgenmangels beim mann

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US (1) US6696432B1 (ja)
EP (1) EP0885005B1 (ja)
JP (1) JP2000506844A (ja)
KR (1) KR19990087573A (ja)
AT (1) ATE247968T1 (ja)
AU (1) AU730777B2 (ja)
BR (1) BR9707844A (ja)
CA (1) CA2248251A1 (ja)
DE (2) DE19610645A1 (ja)
DK (1) DK0885005T3 (ja)
ES (1) ES2206706T3 (ja)
HU (1) HUP9901505A3 (ja)
IL (1) IL125821A0 (ja)
NO (1) NO984075L (ja)
PL (1) PL328709A1 (ja)
PT (1) PT885005E (ja)
WO (1) WO1997032588A2 (ja)
ZA (1) ZA971965B (ja)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002011705A2 (en) * 2000-08-09 2002-02-14 Pharmacia Italia Spa Composition for combined use of aromatase inhibitors
WO2003082254A1 (en) * 2002-04-03 2003-10-09 Jencap Research Ltd. Pharmaceutical composition comprising an aromatase inhibitor and an estrogen suitable for hormone replacement therapy for a male
EP3116510A4 (en) * 2014-03-10 2017-08-16 Endorecherche, Inc. Treatment of male androgen deficiency symptoms or diseases with sex steroid precursor combined with serm

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003017974A1 (en) * 2001-08-31 2003-03-06 Pantarhei Bioscience B.V. Method of treating benign gynaecological disorders and a pharmaceutical kit for use in such method
AU2012200290B2 (en) * 2005-10-19 2014-08-21 Havah Therapeutics Pty Ltd Reduction of side effects from aromatase inhibitors used for treating breast cancer
WO2007045027A1 (en) 2005-10-19 2007-04-26 Chavah Pty Ltd Reduction of side effects from aromatase inhibitors used for treating breast cancer
AU2006303878B2 (en) * 2005-10-19 2011-10-20 Havah Therapeutics Pty Ltd Reduction of side effects from aromatase inhibitors used for treating breast cancer
US7874032B2 (en) * 2008-06-24 2011-01-25 Vaughn North Method and device for maintaining a side sleeping position
US10213440B2 (en) 2014-08-20 2019-02-26 Professional Compounding Centers Of America (Pcca) Oral transmucosal pharmaceutical compositions including testosterone and an aromatase inhibitor
US9351977B2 (en) 2014-10-22 2016-05-31 Chavah Pty Ltd. Methods of reducing mammographic breast density and/or breast cancer risk
WO2017066827A1 (en) 2015-10-22 2017-04-27 Havah Therapeutics Pty Ltd Methods of reducing mammographic breast density and/or breast cancer risk
CN114599369A (zh) 2019-06-03 2022-06-07 哈瓦赫治疗有限公司 用于递送雄激素剂和芳香酶抑制剂的药物制剂和系统以及使用方法
CN115554403B (zh) * 2022-08-16 2024-03-08 山东大学 类固醇激素dhea作为受体adgrg2激动剂配体的应用

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GB2204490A (en) * 1987-05-06 1988-11-16 Hope City Dehydroepiandrosterone
EP0663402A1 (en) * 1992-09-30 1995-07-19 Teikoku Hormone Mfg. Co., Ltd. Novel 7-substituted oxa- or azasteroid compound
WO1996009057A1 (de) * 1994-09-22 1996-03-28 Schering Aktiengesellschaft Verwendung von aromatasehemmern zur herstellung eines arzneimittels zur behandlung eines relativen androgenmangels beim mann

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US5372996A (en) * 1989-03-10 1994-12-13 Endorecherche, Inc. Method of treatment of androgen-related diseases
KR920703065A (ko) * 1989-07-07 1992-12-17 원본미기재 안드로겐 관련질병의 치료방법

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GB2204490A (en) * 1987-05-06 1988-11-16 Hope City Dehydroepiandrosterone
EP0663402A1 (en) * 1992-09-30 1995-07-19 Teikoku Hormone Mfg. Co., Ltd. Novel 7-substituted oxa- or azasteroid compound
WO1996009057A1 (de) * 1994-09-22 1996-03-28 Schering Aktiengesellschaft Verwendung von aromatasehemmern zur herstellung eines arzneimittels zur behandlung eines relativen androgenmangels beim mann

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COMP. BIOCHEM. PHYSIOL., Bd. 112B, Nr. 4, 1995, Seiten 613-618, XP002036347 S. MOSLEMI ET AL.: "THE SYNTHESIS OF 19-NORANDROSTENEDIONE FROM DEHYDROEPIANDROSTERONE IN EQUINE PLACENTA IS INHBIBITED BY AROMATASE INHIBITORS 4-HYDROXYANDROSTENEDIONE AND FADROZOLE" *
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, Bd. 78, Nr. 6, 1994, Seiten 1360-1367, XP002036346 A.J. MORALES ET AL.: "EFFECTS OF REPLACEMENT DOSE OF DEHYDROEPIANDROSTERONE IN MEN AND WOMEN OF ADVANCING AGE" in der Anmeldung erw{hnt *
STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, Bd. 38, Nr. 2, 1991, Seiten 181-188, XP002036344 J.A.A. GEELEN ET AL.: "SELECTION OF 19-(ETHYLDITHIO)-ANDROST-4-ENE-3,17-DIONE (ORG 30958): A POTENT AROMATASE INHIBITOR IN VIVO" *
THE JOURNAL OF STEROID BIOCHEMISTRY, Bd. 32, Nr. 5, 1989, Seiten 625-631, XP002036343 G.H. DECKERS ET AL.: "AROMATASE INHIBITION IN HYPOPHYSECTOMISED FEMALE RATS: A NOVEL ANIMAL MODEL FOR IN VIVO SCREENING" *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002011705A2 (en) * 2000-08-09 2002-02-14 Pharmacia Italia Spa Composition for combined use of aromatase inhibitors
WO2002011705A3 (en) * 2000-08-09 2002-11-21 Pharmacia Italia Spa Composition for combined use of aromatase inhibitors
WO2003082254A1 (en) * 2002-04-03 2003-10-09 Jencap Research Ltd. Pharmaceutical composition comprising an aromatase inhibitor and an estrogen suitable for hormone replacement therapy for a male
EP3116510A4 (en) * 2014-03-10 2017-08-16 Endorecherche, Inc. Treatment of male androgen deficiency symptoms or diseases with sex steroid precursor combined with serm
US10548903B2 (en) 2014-03-10 2020-02-04 Endorecherche, Inc. Treatment of male androgen deficiency symptoms or diseases with sex steroid precursor combined with SERM

Also Published As

Publication number Publication date
KR19990087573A (ko) 1999-12-27
PT885005E (pt) 2004-01-30
ZA971965B (en) 1997-09-10
BR9707844A (pt) 1999-07-27
DK0885005T3 (da) 2003-12-15
NO984075D0 (no) 1998-09-04
EP0885005A2 (de) 1998-12-23
HUP9901505A2 (hu) 1999-09-28
DE19610645A1 (de) 1997-09-11
IL125821A0 (en) 1999-04-11
EP0885005B1 (de) 2003-08-27
WO1997032588A3 (de) 1997-10-16
AU730777B2 (en) 2001-03-15
US6696432B1 (en) 2004-02-24
PL328709A1 (en) 1999-02-15
JP2000506844A (ja) 2000-06-06
NO984075L (no) 1998-09-04
CA2248251A1 (en) 1997-09-12
DE59710660D1 (de) 2003-10-02
ES2206706T3 (es) 2004-05-16
AU2690297A (en) 1997-09-22
ATE247968T1 (de) 2003-09-15
HUP9901505A3 (en) 2000-05-29

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